Biomarker modulation/COX-2 inhibitor/Breast Cancer

说明(申请人提供)乳腺癌仍然是一个主要的健康问题，尽管在早期发现和改善治疗方面做出了努力。目前的研究重点是乳腺癌的预防。在这项努力中，他莫昔芬的大型III期化学预防试验显示，雌激素受体(ER)阳性乳腺癌的发生率降低。但是，他莫昔芬对ER阴性乳腺癌的发生没有影响。因此，乳腺癌的化学预防需要他莫昔芬以外的非激素类药物。此外，目前还没有用于乳腺癌预防的有效替代生物标记物。最后，在第二阶段化学预防干预期间，需要开发比核心活检或细针抽吸(FNA)侵入性更小的方法来获取乳腺组织。近年来，环氧合酶-2(COX-2)在乳腺癌和早期乳腺病变中有表达。塞来昔布是一种选择性的环氧合酶-2抑制剂，具有抗增殖和促凋亡的特性。此外，导管灌洗被证明是从乳腺组织中获得导管上皮细胞的一种可行的方法。我们的目标是以试点的方式测试乳腺癌高危女性乳房组织中塞来昔布对生物标记物的调节作用，并开发一种侵入性较小的组织获取方法，以供将来使用第二阶段化学预防干预。具体地说，首先，我们旨在评估环氧合酶-2抑制剂(塞来昔布)对乳腺癌高危女性乳腺组织细胞异型性和增殖(Ki-67、ER、COX-2、HER-2/neu、EGFR、P53)和凋亡标记物(bcl2、15-LOX)的调节作用。其次，我们的目标是比较通过FNA和导管灌洗获得的标本中的乳腺上皮细胞产量和细胞学异型性，并测试评估从乳腺癌高危女性的乳腺组织中获取的导管灌洗液中生物标记物用于未来化学预防干预的可行性。40名高危妇女(既往乳腺癌病史或小叶原位癌病史或估计的5年Gail风险&GT；1.67)将接受基线导管灌洗和随机FNA，以分析细胞学闭锁和上述标志物。然后，女性将接受为期6个月的塞来昔布每日400毫克/次口服治疗，之后将重复导管灌洗和FNA进行相同的标志物分析。Ki-67和其他增殖标记物的减少、细胞凋亡性标记物的增加和异型性的逆转将为我们提供初步数据，以继续我们计划的第二阶段，即塞来昔布的安慰剂对照化学预防研究。最终，非激素化学预防药物的开发和替代标记物的识别将使我们能够计划以癌症发病率为终点的大规模第三阶段化学预防研究。

DESCRIPTION (provided by applicant)Breast cancer continues to be a major health problem despite efforts in early detection and improvements in treatment. Current research focus is now on the prevention of breast cancer. In that effort, a large phase III chemoprevention trial of tamoxifen showed a reduced incidence of estrogen receptor (ER) positive breast cancer. But, tamoxifen had no impact on the development of ER negative breast cancers. Therefore, non-hormonal agents beside tamoxifen are needed for the chemoprevention of breast cancer. Furthermore, currently there are no validated surrogate biomarkers for the use of breast cancer prevention. Finally, less invasive methods than core biopsies or fine needle aspirations (FNA) need to be developed for breast tissue acquisition during phase II chemopreventive interventions. Recently, Cyclooxygenase 2 (COX-2) expression has been observed in breast cancer and early breast lesions. Celecoxib is a selective COX-2 inhibitor that has antiproliferative and proapoptotic properties. In addition, ductal lavage was recently shown to be a feasible way to obtain ductal epithelial cells from the breast tissue. Our goal is to test, in a pilot fashion, the modulation of biomarkers in response to celecoxib in breast tissue of women who are at high risk for breast cancer and to develop a less invasive tissue acquisition method for the future use of phase II chemopreventive interventions. Specifically, first, we aim to evaluate cyclooxygenase-2 inhibitor (celecoxib) induced modulation of cytologic atypia, and modulation of proliferation (ki-67, ER, COX-2, Her-2/neu, EGFR, p53) and apoptosis markers (bcl-2, 15-LOX) in breast tissue of women who are high risk to develop breast cancer. Second, we aim to compare breast epithelial cell yield and cytologic atypia in specimens obtained via FNA versus ductal lavage and test the feasibility of evaluating biomarkers in ductal lavage fluid obtained from breast tissue of women at high risk for breast cancer for the use of future chemopreventive interventions. Forty high-risk women (history of previous breast cancer or history of lobular carcinoma in situ or estimated 5 year Gail risk > 1.67) will undergo basline ductal lavage and random FNA for the analysis of cytologic atyipia and above-mentioned markers. Women then will be treated with celecoxib 400 mg/day BID per oral for 6 months, after which the ductal lavage and FNA will be repeated for the same marker analyses. Demonstration of a decrease in Ki-67 and other proliferation markers, increase in apopototic markers and reversal of atypia will provide us with preliminary data to proceed with our planned phase II, placebo controlled chemoprevention study with celecoxib. Ultimately, the development of non-hormonal chemoprevention agents, and identification of surrogate markers will allow us to plan large-scale, phase III chemoprevention studies with the endpoint of cancer incidence.